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NM_000372.5(TYR):c.1037-7T>A AND Oculocutaneous albinism

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Feb 14, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000287375.18

Allele description [Variation Report for NM_000372.5(TYR):c.1037-7T>A]

NM_000372.5(TYR):c.1037-7T>A

Gene:
TYR:tyrosinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q14.3
Genomic location:
Preferred name:
NM_000372.5(TYR):c.1037-7T>A
HGVS:
  • NC_000011.10:g.89227816T>A
  • NG_008748.1:g.54945T>A
  • NM_000372.5:c.1037-7T>AMANE SELECT
  • NC_000011.9:g.88960984T>A
  • NM_000372.4:c.1037-7T>A
  • NM_000372.4:c.[1037-7T>A]
Links:
dbSNP: rs61754381
NCBI 1000 Genomes Browser:
rs61754381
Molecular consequence:
  • NM_000372.5:c.1037-7T>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
2

Condition(s)

Name:
Oculocutaneous albinism
Identifiers:
MONDO: MONDO:0018910; MedGen: C0078918; OMIM: PS203100

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000374873Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Pathogenic
(Apr 27, 2017)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000966870Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Feb 7, 2018)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV003844689Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Feb 14, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided22not providednot providednot providedclinical testing

Citations

PubMed

A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism.

Wei A, Wang Y, Long Y, Wang Y, Guo X, Zhou Z, Zhu W, Liu J, Bian X, Lian S, Li W.

J Invest Dermatol. 2010 Mar;130(3):716-24. doi: 10.1038/jid.2009.339. Epub 2009 Oct 29.

PubMed [citation]
PMID:
19865097

Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism.

Gr√łnskov K, Ek J, Sand A, Scheller R, Bygum A, Brixen K, Brondum-Nielsen K, Rosenberg T.

Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1058-64. doi: 10.1167/iovs.08-2639. Epub 2008 Dec 5.

PubMed [citation]
PMID:
19060277
See all PubMed Citations (15)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000374873.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The TYR c.1037-7T>A splice-region variant has been reported in a total of 17 patients with oculocutaneous albinism (OCA), including three homozygotes, eleven compound heterozygotes, and three heterozygotes from a total of 264 affected Caucasian individuals (Hutton et al. 2008; Hutton et al. 2008; Gronskov et al. 2009; Gargiulo et al. 2011). Amongst individuals of Asian ancestry, this variant has been observed in cis with another intronic variant, c.1037-10delTT. This double variant has been reported in at least 13 affected individuals, including 11 compound heterozygotes and two heterozygotes, from a total of 194 affected Asian individuals (Goto et al. 2004; Wei et al. 2010; Ko et al. 2012; Lin et al. 2014; Wang et al. 2015). The c.1037-7T>A variant was absent from over 300 total controls, but is reported at a frequency of 0.00434 in the admixed American population of the 1000 Genomes Project. Using an in vitro assay in A375 cells, Goto et al. (2004) demonstrated that the c.1037-7T>A/c.1037-10delTT double variant causes abnormal splicing. Based on the evidence, the c.1037-7T>A variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966870.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (13)

Description

The c.1037-7T>A (NM_000372.4) variant in TYR has been reported in at least 9 hom ozygous and 16 compound heterozygous individuals with oculocutaneous albinism ty pe 1 (OCA1) and segregated in an affected family member (Hutton 2008a, Hutton 2 008b, Gronskov 2009, Gargiulo 2011, Shahzad 2017, Fabos 2017, and Gao 2017). It has been reported as likely pathogenic or pathogenic in ClinVar (Variation ID#99 527) by multiple laboratories. This variant has been identified in 0.04% (49/126 ,124) of European chromosomes by the Genome Aggregation Database (gnomAD http:// gnomAD.broadinstitute.org; dbSNP rs61754381). This variant has also been identif ied in 1.5% (159/10108) of Ashkenazi chromosomes including 1 homozygote by the G enome Aggregation Database (gnomAD http://gnomAD.broadinstitute.org; dbSNP rs617 54381), which is consistent with some evidence suggesting it may be a founder mu tation in this population (Blumenfeld 2008, conference abstract: http://iovs.arv ojournals.org/article.aspx?articleid=2376752). This variant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are needed to fully establish its clinical significanc e, this variant is likely as pathogenic for OCA1 in an autosomal recessive manne r based upon multiple biallelic case observations and segregation in affected in dividuals. ACMG/AMP Criteria applied: PM3_VS, PS3_M.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844689.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: TYR c.1037-7T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site and one predicts the variant weakens the 3' acceptor site. Four predict the variant creates a new 3' acceptor site upstream from the canonical splice site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing by generating an abnormal splicing site, resulting in the insertion of 4 nucleotides which creates a premature termination codon downstream (e.g. Goto_2004). The variant allele was found at a frequency of 0.00095 in 249548 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00095 vs 0.0056), allowing no conclusion about variant significance. c.1037-7T>A has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Oculocutaneous Albinism (e.g. Goto_2004, Lasseaux_2018). These data indicate that the variant is very likely to be associated with disease. Twenty-one submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=19)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024